The invention relates to HIV and FIV protease inhibitors. More particularly, the invention is directed to HIV and FIV protease inhibitors characterized by core structures having a small P3 residue. The invention is also directed to methods for making such compounds with clinically useful activity and which are potentially resistive against loss of inhibitory activity due to development of resistant strains of HIV.
The aspartyl protease (PR) of human immunodeficiency virus (HIV) has been the subject of extensive research for the development of therapeutically useful inhibitors to control the progression of human acquired immunodeficiency syndrome (AIDS). Four competitive inhibitors of this enzyme have been approved and several others are in clinical trials (Babine et al. Chem. Rev. 1997, 97, 1359-1472; De Lucca et al. Drug Discovery Today 1997, 2, 6-18; Vacca et al. Drug Discovery Today 1997, 2, 261-272; Huff et al. J. Med. Chem. 1991, 34, 2305; Wlodawer et al. Ann. Rev. Biochem. 1993, 62, 543-585). Despite the high potency and high selectivity of these inhibitors used in AIDS therapy, many drug-resistant variants of HIV have been identified, including 45 distinct drug-resistant variants found in the past 3 years.
The drug-resistant mutants are generated through incomplete suppression of the virus by inhibitors clinically and usually contain multiple substitutions in their proteases. Moreover, these mutant enzymes often exhibit cross-resistance to many structurally distinct protease inhibitors. Therefore, development of new broad-based protease inhibitors efficacious against a wide spectrum of HIV variants may be necessary in order to slow down the development of drug resistance (Schinazi et al. Int. Antiviral News 1997, 5, 129-142; Wilson et al. J. Biochim. Biophy. Acta 1997, 1339, 113-125; Erickson et al. Annu. Rev. Pharmacol. Toxicol. 1996, 36, 545-571; Gulnik et al. Biochemistry 1995, 34, 9282-9287; Erickson et al. Nature Struct. Biol. 1995, 2, 523-529; Condra et al. Nature, 1995, 374, 569-571; Otto et al. Proc. Natl. Acad. Sci. USA 1993, 90, 7543-7547; Wong et al. Science, 1997, 278, 1291-1295; Finzi et al. Science, 1997, 278, 1295-1300).
FIV is a retrovirus which causes an immunodeficiency syndrome in cats comparable to AIDS in humans (Talbott et al. Proc. Natl. Acad. Sci. USA 1989, 86, 5743-5747; Pedersen et al. Science 1987, 235, 790-793). Both HIV and FIV PRs are C2-symmetric homodimeric enzymes, and they have almost superimposable active-site structures that facilitate catalysis by an identical mechanism (Slee et al. J. Am. Chem. Soc. 1995, 117, 11867-11878). Similar to HIV PR, FIV PR also processes both structural proteins of gag and the enzymes encoded by pol during FIV replication (Kramer et al. Science 1986, 231, 1580-1584) Furthermore, six mutated residues in HIV PR causing drug resistance (K20I, V32I, I50V, N88D, L90M, Q92K; Mellors et al. Int. Antiviral News, 1995, 3, 8-13) are found in the structurally aligned native residues of FIV PR.
Kinetic studies have also demonstrated that various potent HIV PR inhibitors which interact with the binding region from S4 to S4xe2x80x2 are less efficient inhibitors of FIV PR by a factor of 100 or more and good inhibitiors of FIV PR are often better inhibitors of the wild-type and drug-resistant HIV PRs. In addition to the observation that FIV PR resembles many known drug-resistant HIV PRs, the cat offers a potential animal system to test the effectiveness of anti-lentiviral agents in vivo to speed up the drug development process.
What is needed are combinatorial libraries of HIV and FIV protease inhibitors and simple synthetic methods for making same.
Furthermore, what is needed is a class of HIV and FIV protease inhibitors having enhanced possibilities of variability at the binding region for improving binding between the enzyme and its inhibitor.
Finally, what is needed are new HIV and FIV protease inhibitors having clinically useful inhibitory activity and a resistivity to a loss of inhibitory activity due to development of resistant strains of HIV.
One aspect of the invention is directed to a protease inhibitor represented by the following structure: 
In the above structure, R1 may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-alanine-asparagine-, carbobenzyloxy-threonine-valine- and carbobenzyloxy-valine-valine-. R2 may be any of the following radicals: xe2x80x94CH2-Phenyl, and xe2x80x94CH2xe2x80x94CH(CH3)2. R3 may be any of the following radicals: hydrogen, oxygen and hydroxyl; R4 is selected from the group consisting of hydrogen, oxygen and hydroxyl, wherein R3 and R4 are not both hydroxyl and wherein R3 and R4 are either a single combined oxygen forming a carbonyl group. R5 may be any of the following radicals: hydrogen, and oxygen; R6 is selected from the group consisting of hydrogen, and oxygen, wherein R5 and R6 are either a single combined oxygen forming a carbonyl group or both seperately hydrogen. R7 is a radical represented by the formula: 
wherein R8 is a radical selected from the group consisting of xe2x80x94(H)2, and xe2x80x94H(t-Butyl).
Another aspect of the invention is directed to a protease inhibitor represented by the following structure: 
In the above structure, R1 may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine-, carbobenzyloxy-alanine-asparagine- and carbobenzyloxy-valine-valine-. R2 may be any of the following radicals: xe2x80x94CH2-Phenyl, and xe2x80x94CH2xe2x80x94CH(CH3)2. R3 is either hydrogen or xe2x80x94OH.
Another aspect of the invention is directed to a protease inhibitor represented by the following structure: 
In the above structure, R1 may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine- , carbobenzyloxy-alanine-asparagine- and carbobenzyloxy-valine-valine-. R2 is either xe2x80x94(H)2 or xe2x80x94H(t-Butyl).
Another aspect of the invention is directed to a protease inhibitor represented by the following structure: 
In the above structure, R1 may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine-, carbobenzyloxy-valine-valine- and carbobenzyloxy-alanine-asparagine-.
Another aspect of the invention is directed to protease inhibitor represented by the following structure: 
In the above structure, R1 may be any of the following radicals: hydrogen, carbobenzyloxy-, carbobenzyloxy-valine-, carbobenzyloxy-glycine-valine-, carbobenzyloxy-alanine-valine-, carbobenzyloxy-leucine-valine-, carbobenzyloxy-phenylalanine-valine-, carbobenzyloxy-serine-valine-, carbobenzyloxy-threonine-valine-, carbobenzyloxy-valine-valine- and carbobenzyloxy-alanine-asparagine-.